Download Diurnal variations of the dominant cycle length of chronic atrial

Am J Physiol Heart Circ Physiol
280: H401–H406, 2001.
Diurnal variations of the dominant cycle length
of chronic atrial fibrillation
CARL J. MEURLING,1 JOHAN E. P. WAKTARE,2 FREDRIK HOLMQVIST,1 ANTTI HEDMAN,3
A. JOHN CAMM,2 S. BERTIL OLSSON,1 AND MAREK MALIK2
1
Department of Cardiology, Lund University Hospital, Lund, Sweden; 2Department of Cardiological
Sciences, St. George’s Hospital Medical School, London, United Kingdom; and 3Department
of Medicine, Kuopio University Hospital, Kuopio, Finland
Received 11 February 2000; accepted in final form 2 August 2000
normal sinus rhythm (6, 13). In atrial fibrillation (AF),
atrial refractoriness is shortened compared with sinus
rhythm, but whether it exhibits diurnal variability is
unknown. Heart rate during AF is determined by the
atrioventricular (AV) nodal conduction (4), but a modulating effect of atrial inputs has been suggested (22,
26).
The aim of this study was to noninvasively detect the
presence and to characterize the nature of diurnal
variations in atrial electrophysiology during chronic
AF. We sought to determine the relationship between
fluctuations in AF cycle length and heart rate. The
study utilized a noninvasive method, frequency analysis of fibrillatory electrocardiogram (FAF-ECG), which
has been validated as a technology for the measurement of atrial cycle length during AF (11).
METHODS
in humans ranges from shortterm modulations at frequencies corresponding to respiration to significant low-frequency diurnal fluctuations (1, 10, 28). Fluctuations in autonomic nervous
system tone acting on the sinus node are an important
underlying mechanism (1), but humoral efferent systems are also active (31, 34). However, the whole organism acts as a complex biological system, with diurnal fluctuations in many other parameters such as
temperature, blood pressure, metabolism, and activity
levels. These may also directly or indirectly alter heart
rate.
Diurnal fluctuations in atrial refractoriness have
been little studied, but it is well recognized that autonomic tone has a profound effect on refractoriness in
Study population and data acquisition. Recruited patients
had chronic (persistent or permanent) AF of ⬎1 mo duration.
Exclusion criteria were pharmacological treatment with
␤-blockers, antiarrhythmic drugs (Ia, Ib, Ic, III), or sympathomimetic agents, diabetes mellitus, overt heart failure,
previous cerebrovascular events, or conditions that would
possibly cause interference with the autonomic nervous system, such as current alcohol abuse. The study was approved
by the local Ethics Committee, and all patients gave written
informed consent.
The study investigated 21 outpatients (15 men, mean age
64 ⫾ 12 yr, range 34–78 yr). The median duration of AF was
12 mo (range 1–120 mo), and subjects had undergone a mean
of one previous unsuccessful cardioversion (none in 6 patients, 1 in 11 patients, 2 in 2 patients, and 3 in 2 patients).
Drug therapy included digoxin in 14 patients, an angiotensin-converting enzyme inhibitor in 8, diltiazem in 3, and
verapamil in 1. At echocardiography, left ventricular function was normal in 19 patients and slightly impaired in 2.
The mean left atrial diameter was 47 ⫾ 7 mm (range 36–66
mm).
Long-term ECG was recorded in each patient using a
digital three-channel Holter recorder (6632 Altair-DISC
recorder, SpaceLabs Burdick, East Syracuse, NY) with a
Address for reprint requests and other correspondence: J. E. P.
Waktare, Cardiological Sciences, St. George’s Hospital Medical
School, Cramner Terrace, London SW17 0RE, UK (E-mail: jwaktare
@sghms.ac.uk).
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
autonomic nervous system; circadian rhythms
VARIABILITY OF HEART RATE
http://www.ajpheart.org
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society
H401
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Meurling, Carl J., Johan E. P. Waktare, Fredrik
Holmqvist, Antti Hedman, A. John Camm, S. Bertil
Olsson, and Marek Malik. Diurnal variations of the dominant cycle length of chronic atrial fibrillation. Am J Physiol
Heart Circ Physiol 280: H401–H406, 2001.—High-resolution
digital Holter recording was carried out in 21 patients (15
men, 64 ⫾ 12 yr) with chronic atrial fibrillation. Dominating
atrial cycle length (DACL) was derived by frequency domain
analysis of QRST-reduced electrocardiograms. Daytime
mean DACL was 150 ⫾ 17 ms, and nighttime mean was
157 ⫾ 22 ms (P ⫽ 0.0002). Diurnal fluctuation in DACL
differed among patients: it tended to be virtually absent in
those with a short mean DACL, but in those with longer
DACL the night-day difference was as much as 23 ms (R ⫽
0.72, P ⬍ 0.001, correlation of mean DACL to night-day
difference). Mean DACL also correlated with ventricular
cycle length (R ⫽ 0.40, P ⬍ 0.001), particularly at night (r ⫽
0.49). The shorter cycle lengths found in this study during
the day are consistent with sympathetic and/or other physiological modulation, but since increased vagal tone shortens
atrial refractoriness in most models, parasympathetic influences are not likely to play a major role. Alternatively, atrial
effective refractory period may not be the sole determinant of
atrial cycle length during atrial fibrillation.
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DIURNAL VARIABILITY OF ATRIAL FIBRILLATION
Fig. 1. Graphic summary of the signal processing method. A: within
the raw ECG signal, QRS complexes and T waves are identified and
optimally aligned. B: once all QRS complexes are identified, an
appropriate inverted QRST template is subtracted to leave a residual signal comprising pure atrial fibrillatory activity (C). This signal
is subjected to high- and low-pass filtering and is downsampled
before the estimation of a frequency power spectrum using fast
Fourier transform (D). (See Ref. 11 for full description of the method,
including filter and Fourier transform parameters.)
RESULTS
Data availability. One patient was excluded because
the recording contained only 2 h that could be analyzed. The calculations were made on the basis of the
remaining 20 patients.
The mean duration of analyzable recording was
15.5 h (range 12–16 h). The median starting hour was
1500 (range 0700–1700), and the finishing hour was
0600 (range 0100–2100). Of the potential 310 sequences of 5 min each, a segment suitable for analysis
was found in 305 (98%) cases. The median offset from
the hour to the beginning of the segments was 5 min
(range 0–30 min), with the daytime median offset (7
min) being larger than the nighttime offset (2 min).
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sampling rate of 1 kHz and an amplitude resolution of 0.16
␮V over a ⫾5-mV range for 17 h. Leads were positioned
using a novel quasi-orthogonal three-lead configuration
(35), which optimizes acquisition of atrial signal in bipolar
recordings.
For analyses of day-night differences, night was defined as
2330–0630 and day as 0730–2130.
Signal processing. The Holter recordings were transferred
to a personal computer for standard automated analysis,
visual inspection, overreading, and manual correction using
commercial software (Vision Premier, SpaceLabs Burdick). A
5-min segment was further chosen in each hour of each
recording. The search for such a segment and, subsequently,
in the analysis of atrial cycle length was driven by the quality
of the original. The same procedure was repeated for each
hour of each recording. Initially, the segment of the first 5
min of the hour was taken. If there was low signal-to-noise
ratio (i.e., noise amplitude similar to fibrillatory wave amplitude), more than 2% high-amplitude noise (noise ⱖ R-wave
amplitude), or baseline wander, the segment was rejected. In
such a case, the preceding and following 5-min regions were
inspected to identify the closest segment of acceptable quality. If none could be found, the hour was rejected.
The selected 5-min segments were analyzed using the
FAF-ECG method, which has been described in detail elsewhere (11). Briefly, QRST complexes were subtracted, and
frequency domain analysis was performed on the residual
ECG signal within the 3- to 12-Hz range using a fast Fourier
transform. The peak frequency in the generated spectrum,
expressed as a cycle length, constituted the dominant atrial
cycle length (DACL). The method is illustrated in Fig. 1. For
this analysis the DACL was obtained from a bipolar lead with
the positive electrode at a low C1 position (6th intercostal
space, right sternal border) and with the indifferent electrode
in a left subclavicular position (35). This lead has a superior
atrial signal resolution and corresponds approximately to the
conventional unipolar V1 lead, in which the DACL has been
shown to correlate closely with invasively measured right
atrial free wall fibrillatory cycle length (11).
All frequency spectra were visually inspected to confirm
sufficient quality allowing an accurate DACL determination.
Optimum-quality spectra exhibit a single sharp spectral
peak in the expected range for DACL (5–11 Hz) with minimum low-frequency components in the 3- to 5-Hz range
(⬍50% of DACL power). Spectra were of acceptable quality in
the presence of a single spectral peak with low-frequency
components with power between 50 and 150% of the DACL
power. Where two spectral peaks were present within the 3to 12-Hz band, the component with the highest amplitude
was automatically chosen by the FAF-ECG software, but all
such cases were manually confirmed.
Heart rate was expressed as mean R-R interval, calculated
by the commercial Holter software for each 5-min segment.
Statistics. Unless otherwise specified, values are means ⫾
SD. Wilcoxon test was used for comparison between paired
samples. Spearman ranked correlation coefficients and the U
test were used elsewhere. Since there was significant variation between subjects in mean DACL, the hourly DACL
values were normalized for selected analyses. This was performed by dividing the individual DACL values by the mean
of all valid DACL values for the given subject. P ⬍ 0.05 was
considered statistically significant. All statistical analyses
were performed using STATISTICA for Windows (version
5.1, StatSoft, Tulsa, OK).
DIURNAL VARIABILITY OF ATRIAL FIBRILLATION
Manual correction of the DACL was needed on one
analyzed segment (the automated analysis identified
an outlier peak of a bimodal distribution, while the
other peak corresponded to adjacent hours).
Diurnal fluctuations in AF cycle length. Mean DACL
was 154 ⫾ 20 ms but varied significantly between
patients, ranging from 125 to 186 ms, and through the
day (Fig. 2). The DACL exhibited significant diurnal
fluctuations, with a shorter mean DACL during the
day (mean 150 ⫾ 17, range 124–179) than at night
(mean 157 ⫾ 22, range 125–195, P ⫽ 0.0002). There
was significant interpatient variation in the mean
DACL for the recording. The normalized DACL values
are presented in Fig. 3.
There was a significant correlation between mean
DACL and the standard deviation of DACL values for
patients (r ⫽ 0.78, P ⫽ 0.00004), with longer DACL
being associated with a greater standard deviation
Fig. 3. Diurnal fluctuation of the DACL. The DACL has been normalized using the mean DACL for each individual patient. For each
hour, the mean, SE, and SD values are shown. The curve is a
third-order polynomial fit to the means.
(i.e., the DACL variability increased with increasing
DACL values). Likewise, the magnitude of the difference between daytime and nighttime mean DACL was
strongly related to the mean DACL (Fig. 4). Those
patients with short DACL exhibited little diurnal variation, while those with longer mean DACL exhibited
night-day differences of up to 23 ms (P ⫽ 0.0004; Fig.
4).
Of the patient characteristics studied, none showed a
significant relationship with the mean DACL or with
the magnitude of the night-day difference (Table 1).
Relationship between fluctuations in AF cycle length
and heart rate. There was a significant correlation
between the mean R-R interval and DACL (r ⫽ 0.30,
P ⬍ 0.000001), with long DACL corresponding to long
R-R intervals. The correlation was higher during the
night (r ⫽ 0.44, P ⫽ 0.000001) than during the day (r ⫽
0.27, P ⫽ 0.001; Fig. 5).
DISCUSSION
This study has shown that 1) the AF cycle length
during chronic AF exhibits diurnal variability, with
longer cycle lengths (i.e., slower AF revolution) occurring at night; 2) there is a correlation between the AF
cycle length and ventricular cycle length, particularly
at night; and 3) there are marked interpatient differences in the diurnal variability of the AF cycle length,
with higher variability in patients with a longer mean
AF cycle length.
Diurnal rhythms and changes in AF cycle length. The
diurnal pattern of variation of atrial cycle length found
in this study is in keeping with circadian changes in
atrial refractoriness during sinus rhythm (6) and atrial
pacing (6, 13). Previous work has shown that atrial
cycle length closely correlates with atrial refractory
period during AF (15, 17, 36), and the former may
therefore be used as an index of the latter. However,
this has been tested in laboratory conditions and has
not been validated under varying autonomic influences
or other diurnal physiological variations.
Fig. 4. Relationship between mean DACL and the magnitude of the
night-day difference in mean DACL.
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Fig. 2. Individual diurnal fluctuations in dominating atrial cycle
length (DACL) in 20 patients.
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DIURNAL VARIABILITY OF ATRIAL FIBRILLATION
Table 1. Influence of recorded variables on mean
DACL and night-day differences in DACL
DACL, ms
Feature absent
Digoxin treatment
ACE inhibitor treatment
Normal LV function
AF duration ⬎ mean
Age ⬎ mean
LA diameter ⬎ mean
Feature present
Mean
DACL
N-D
difference
Mean
DACL
N-D
difference
152
159
181
155
149
155
8
8
6
7
7
6
156
147
153
154
170
155
7
6
7
9
9
8
A circadian rhythm is seen in a range of physiological variables, including arterial (24) and pulmonary
(19) blood pressure, body temperature, blood pH, hormone levels (25, 31, 34), and autonomic tone (10, 12).
Furthermore, there are diurnal differences in levels of
physical exertion, respiratory rate, and body posture. A
number of these factors are likely to be interrelated
and may contribute to diurnal changes in atrial electrophysiology. However, a physiologically plausible direct effector mechanism exists probably for only four
modulators, i.e., autonomic modulations, including
those due to postural changes, core body temperature,
atrial stretch, and hormonal changes.
Temperature-induced changes in cardiac refractory
period are demonstrable (32) but are mainly seen with
major body temperature alterations, rather than with
small physiological fluctuations. The effect of atrial
stretch on atrial effective refractory period has been
studied by AV synchronous pacing (3, 16), which has
additional hemodynamic effects. Klein et al. (16) found
a strong correlation between changes in atrial effective
refractory period and both right atrial pressure and left
atrial diameter. In contrast, Calkins et al. (3) found no
such effect with or without prior autonomic blockade.
Data from isolated cell preparations suggest that significant changes in cardiac refractory period occur only
at supraphysiological levels of stretch (27). The levels
of circulating catecholamines may affect atrial electrophysiology. However, catecholamine levels are intrinsically linked to other parts of the autonomic nervous
system, and no data are available on electrophysiological effects of other diurnally varying hormones. Hence,
it seems plausible to propose that the observed diurnal
changes in atrial cycle length are largely mediated by
autonomic tone fluctuations.
Increased sympathetic and vagal tone decreases the
atrial refractory period (20, 30, 38), but the effect of
electrophysiological properties on fibrillating human
atrial tissue is less clear. Some recent data suggest
that the chronic fibrillating atrium is more under sympathetic than vagal control (26, 33), but other studies
have shown that adrenergic compounds do not affect
Fig. 5. Relationship between ventricular rate (x-axis) and DACL
(y-axis) at night (A) and during the day (B). Relationship is stronger
at night, with a steeper slope of the regression line.
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DACL, dominant atrial cycle length; ACE, angiotensin-converting
enzyme; LV, left ventricular; AF, atrial fibrillation; LA, left atrial;
N-D, night-day. All differences are nonsignificant (P ⬎ 0.05, U test
for discrete state variables, Spearman R ranked correlation coefficient for other variables).
the chronically fibrillating atrium (32). Unless increased vagal tone has the opposite effect during AF to
that observed in normal conditions, the present study
supports the hypothesis that either the sympathetic
tone is the dominant determinant of changes in atrial
cycle length during AF or dominant AF cycle frequency
is less closely determined by atrial effective refractory
period than is presently presumed. Preserved vagal
tone is known to offer an antiarrhythmic defense in the
ventricle. Hence, it might exhibit similar effects in the
fibrillating atria, e.g., by slowing and/or partially
blocking excitation propagation. In such a scenario, an
excitable gap of a larger-than-negligible size may exist
within fibrillating atrium under dominant vagal influence.
In the present study, the variation in refractoriness
appeared to show a single diurnal peak, but more
complex patterns of circadian fluctuations in atrial
electrophysiology have been suggested to occur. Yamashita et al. (37) found that the probability of paroxysmal AF onset, maintenance, and termination had
diurnal distributions that varied from a single peak to
DIURNAL VARIABILITY OF ATRIAL FIBRILLATION
period are involved. It is believed that concealed conduction of the AF impulses into the AV node and
electrotonic modulation of AV nodal propagation participate in the determination of ventricular rate (22).
The present study found that the net result is a direct
relationship between atrial and ventricular cycle
length in physiological conditions.
Limitations of the study. The study used 17-h, rather
than 24-h, Holter recordings, a limitation imposed by
the technology available. Although no statistical differences between different daytime and different nighttime hours could be found (data not shown), we cannot
exclude an effect of the underrepresentation of certain
daytime segments. Because of the variable quality of
ambulatory recordings, we were unable to select segments precisely on the hour in a large proportion of
segments. Segments during any activity beyond mild
exertion are likely to have been unsuitable for analysis,
leading to an underestimation of true diurnal changes.
The study also required some operator selection, and
despite the objective criteria applied, this may have
introduced bias.
The FAF-ECG method was validated in controlled
laboratory settings on supine subjects, and thus a
confounding effect of posture, activity, or other variables is possible. However, the quality of spectra
(amount of low-frequency signal, sharpness of peaks)
in this study was comparable to that in previous studies. Moreover, there are no signal modulations likely to
be encountered during ambulatory recordings that fall
within the examined frequency range. It is therefore
unlikely that the findings were due to confounding
factors, rather than to alterations in AF cycle length.
The precise intracardiac site corresponding to the
DACL from the lead used in this study has not been
tested but is likely to be the right atrial free wall.
Assessment of other parts of the atria was therefore
not performed. Finally, the DACL can only be used as
an assessment of atrial refractoriness as long as there
are no significant changes in atrial conduction velocity.
The authors thank Burak Acar (Dept. of Electrical and Electronics
Engineering, Bilkent University, Ankara, Turkey) for help with
computer programming.
This study was supported by grants from the Swedish Society of
Cardiology, Swedish Heart Lung Foundation, and Medical Faculty of
Lund University. J. E. P. Waktare is supported by a British Heart
Foundation Project Grant.
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